LC5A8 was first identified as a candidate tumor suppressor in colon. We showed that it is a Na+-coupled transporter for short-chain fatty acids (SCFAs) and that its ability to energize the cellular entry of the SCFA butyrate, a bacterial fermentation product of dietary fiber and an inhibitor of histone deacetylases, underlies its tumor-suppressive function in colon. However, in vivo studies with Slc5a8-/- mice failed to support such a function. Now we found that the ability of Slc5a8 to protect against colitis and colon cancer is dictated by dietary fiber content. The transporter is obligatory for the beneficial effects of SCFAs in colonic epithelial cells only when the luminal concentrations of SCFAs are low (low fiber intake). In contrast, the obligatory role of the transporter in mucosal immune cells is not dependent on dietary fiber content. We hypothesize that SLC5A8 is a conditional tumor suppressor in colon and is essential for the maintenance of the tolerogenic phenotype of the mucosal immune system, but the obligation of its role in colonic epithelial cells and LP immune cells is differentially influenced by the dietary fiber content. In addition, we hypothesize that SLC5A8 and optimal dietary fiber protect against bacterial dysbiosis in the gut, which is known to drive inflammation and cancer in colon. We will test these hypotheses by completing the following specific aims: (1A) Show that Slc5a8 is essential for the immunotolerant phenotype of the mucosal immune system by qualitatively and quantitatively increasing the number of anti- inflammatory dendritic cells and immunosuppressive Tregs in colon, and determine the relevance of dietary fiber content to this process; (1B) Delineate the phylogenetic profile of gut microbiota in wild type and Slc5a8-/- mice under low-fiber & high-fiber conditions to determine if bacterial dysbiosis occurs in the gut as a consequence of Slc5a8 deletion and/or low dietary fiber, thus driving the increased severity of colitis and enhanced colon cancer observed in Slc5a8-/- mice under low-fiber dietary conditions; (2A) Interrogate the contribution of Slc5a8 in colonic epithelial cells versus Slc5a8 in myeloid cells to the protection against experimental colitis under low-fiber & high-fiber dietary conditions using conditional knockout mice with selective deletion of Slc5a8 either in epithelial cells or in myeloid cells; (2B) Interrogate the contribution of Slc5a8 in colonic epithelial cells versus Slc5a8 in myeloid cells to the protection against experimental colon cancer under low-fiber & high-fiber dietary conditions using conditional knockout mice with selective deletion of Slc5a8 either in epithelial cells or in myeloi cells; (3) Dissect the changes in histone acetylation and consequent transcriptome landscape in colonic epithelial cells and LP dendritic cells that are responsible for the ability of Slc5a8 to protect against colitis and colon cancer under low-fiber & high-fiber dietary conditions.